UC Riverside

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that heterodimerizes with retinoid X receptor (RXR), binds to PPAR response elements (PPREs), and activates transcription of genes involved in adipogenesis, fatty acid storage, and glucose metabolism. PPARγ-specific pharmaceuticals (e.g., thiazolidinediones) have been developed to treat Type II diabetes within human populations. However, in vitro and in vivo (rodent) studies have demonstrated that PPARγ can also be activated by environmental chemicals. Due to the ubiquitous presence of these environmental chemicals, they pose a potential concern for those chronically exposed via inhalation or ingestion of contaminated dust. However, while the potential role of PPARγ in regulating later stages of development has been explored, it is unclear whether 1) exposure to PPARγ agonists may alter early embryonic developmental processes and 2) downstream impacts on cell signaling and physiology are directly associated with PPARγ activation by drugs and environmental chemicals. Therefore, the primary objectives of this dissertation are to 1) test the hypothesis that exposure to a human PPARγ agonist (ciglitazone) disrupts dorsoventral patterning during early embryonic development within zebrafish, 2) map genomic, transcriptomic, and lipidomic changes in human hepatocarcinoma (HepG2) cells after exposure to a reference PPARγ agonist (ciglitazone) and antagonist (GW 9662), and 3) test the hypothesis that exposure to environmental chemicals (tetrabromobisphenol A and tetrachlorobisphenol A) – suspected PPARγ agonists – results in PPARγ-mediated transcriptional and lipidomic changes within HepG2 cells. For Aim 1, using ciglitazone to activate PPARγ and a pparγ-specific morpholino to knockdown pparγ, we found that ciglitazone affects dorsoventral patterning in developing zebrafish embryos in a PPARγ-independent manner. For Aim 2, using chromatin immunoprecipitation-sequencing, mRNA-sequencing, neutral lipid staining, and lipidomics, we mapped genomic, transcriptomic, and lipidomics changes following exposure to a ciglitazone or GW 9662, but did not find changes at one level to be predictive of changes at other levels. For Aim 3, TBBPA and TCBPA exposure did not result in downstream PPARγ-dependent transcriptomic or neutral lipid changes. Overall, our findings further our understanding about how exogenous PPARγ ligands may alter early embryonic development and affect lipid homeostasis within human cells.